The MSH2 c.942+3A>G (p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with predominantly likely pathogenic submissions, although some submissions classify it as uncertain significance.1 This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 3/11,582 alleles (total AF 0.00025902) with grpmax FAF 0.00004967, which is above the MSH2 VCEP PM2 threshold of less than 0.00002 and below the BS1 threshold of at least 0.0001.2 Published RNA studies reported that this variant disrupts MSH2 donor splicing and generates an exon 5-skipped transcript, supporting a true splice defect despite its non-canonical +3 position.3 SpliceAI predicts a low splice effect with a maximum delta score of 0.02, which is below the MSH2 VCEP PP3 threshold of at least 0.2 and within the BP4 threshold of 0.1 or less, but this in silico result is inconsistent with the published RNA evidence.4
Final classification
Uncertain Significance
PVS1
MSH2
c.942+3A>G
p.?
This variant
The MSH2 c.942+3A>G (p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with predominantly likely pathogenic submissions, although some submissions classify it as uncertain significance.
Official CSPEC/VCEP final-classification framework from final_classification_framework.json (cspec_ruleset criteria-combination framework; Richards et al. 2015 combining rules as represented in the MSH2/InSiGHT specification).
Classification rationale
PVS1
Uncertain Significance
MSH2 c.942+3A>G
PVS1
→
Uncertain Significance
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000251.3 · variants mapped to exon structure
MSH2
NM_000251.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 16 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
PVS1
Strong
review
Pathogenic
Published RNA studies reported that this non-canonical donor-site variant causes skipping of MSH2 exon 5. Exon 5 corresponds to c.793_942 (150 nucleotides), predicting an in-frame deletion of 50 amino acids, p.Gly265_Gln314del. Under the MSH2 VCEP splice-specific PVS1 framework, confirmed aberrant splicing for a non-canonical splice variant supports PVS1 use; a conservative PVS1_Strong assignment is supported, with human review needed to confirm the extent of loss of full-length transcript and final splice consequence weighting.
MSH2 c.942+3A>G was reported to interfere with exon 5 donor splicing and produce an mRNA lacking exon 5.A second RNA-focused study supported that nucleotide substitutions in MSH2 can be the direct cause of splicing defects and used minigene/in vitro transcription approaches.
Assessed · not applied
· 7 not met · 9 not assessed
Pathogenic
PS3
RNA evidence supports a splice defect, but the retrieved evidence does not provide a calibrated MMR functional assay result or a variant-specific functional assay classification mapped through the MMR functional assay flowchart for PS3.
PS2
Published literature notes recurrent de novo occurrence of this variant, but the retrieved evidence does not provide case-level MSH2 VCEP de novo point data with confirmed parentage and qualifying tumor evidence needed for PS2 scoring.
PS1
No evidence was identified in the retrieved materials showing that a different variant affecting this same non-canonical splice nucleotide has already been established by this VCEP as pathogenic or likely pathogenic with similar or worse splicing prediction.
PM2
This variant is present in gnomAD v4.1 with grpmax FAF 0.00004967, which is above the MSH2 VCEP PM2 threshold of less than 0.00002.
PM3
No evidence was identified showing this variant in trans with another pathogenic MMR variant in a case scored under the MSH2 VCEP PM3 framework.
PP3
SpliceAI predicts a low splice effect for this variant, with a maximum delta score of 0.02.
PP4
No case-level microsatellite instability, mismatch repair protein expression, or tumor phenotype data were identified for this individual, so PP4 cannot be scored from the retrieved evidence.
PP1
No segregation dataset with a calculable Bayes likelihood ratio was identified, so PP1 cannot be assessed from the retrieved evidence.
Benign
BA1
The gnomAD v4.1 grpmax FAF for this variant is 0.00004967, which is below the MSH2 VCEP BA1 threshold of at least 0.001.
BS1
The gnomAD v4.1 grpmax FAF for this variant is 0.00004967, which is below the MSH2 VCEP BS1 threshold of at least 0.0001 and less than 0.001.
BS2
No evidence was identified showing this variant in trans with a known pathogenic MSH2 variant in a qualifying individual without clinical manifestations of CMMRD, so BS2 cannot be assessed.
BS3
Available RNA studies reported an abnormal splicing effect for this variant, with exon 5 skipping, rather than no mRNA aberration.
BS4
No lack-of-segregation dataset with a Bayes likelihood ratio was identified, so BS4 cannot be assessed from the retrieved evidence.
BP4
SpliceAI predicts a low splice effect for this variant, with a maximum delta score of 0.02, which is below the BP4 threshold of 0.1 or less.
BP5
No tumor series showing mismatch between tumor findings and the gene harboring this variant were identified, so BP5 cannot be assessed.
BP7
This intronic variant is at position c.942+3, which is closer to the splice donor site than the MSH2 VCEP BP7 boundary of +7 or beyond.
N/A · 11
PS4 · PM5 · PM6 · PM1 · PP2 · PP5 · BP6 · BP3 · BP2 · BP1 · PM4
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000259023; MAF= 0.02590%, 3/11582 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.00225225; MAF= 0.22523%, 1/444 alleles, homozygotes = 0); grpmax FAF= 4.967e-05.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.026%
· 3 / 11,582
0 hom · FAF 0.005%
0 hom · FAF 0.005%
Remaining individuals 1 / 444 |
0.23% |
European (non-Finnish) 2 / 7,044 |
0.028% |
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (5 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as likely pathogenic (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Recurrent germline mutation in MSH2 arises frequently de novo.
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
Strong
Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mut
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
Strong
Sources & reference links